Influenza is an acute febrile illness caused by influenza virus respiratory infection. Influenza viruses are classified into A, B, and C types depending on differences in surface structural proteins. There are slight differences in host, epidemiology and clinical features among the types of influenza viruses. Influenza virus is a spherical virus with a diameter of 80-120 nm, whose subtypes are determined based on the type of hemagglutinin (HA) and neuraminidase (NA) glycoproteins exposed on the surface. Subtypes are classified mainly with regard to type A influenza. Currently, there have been found 16 types of HA from H1 to H16 and 9 types of NA from N1 to N9, and a total of 144 subtypes (for example, H1N1 and H1N2) exist in type A influenza even based on a simple calculation. Influenza causes new big and small epidemics every year through antigen variations. Antigen variations include antigenic shift (e.g., H3N2→H2N2) in which HA or NA is replaced with new HA or NA resulting in subtype alteration, and antigenic drift in which point mutations take place in existing HA and NA genes. Antigen drift, which occurs almost every year in influenza A or B type, causes seasonal epidemic.
Among HA and NA surface antigens, immunization against HA is particularly associated with influenza prevention and disease severity. Therefore, neutralizing antibodies produced in a body against hemagglutinin, which is the most important component of the influenza vaccine, play a crucial role in the prevention of influenza virus infection. Influenza vaccines include inactivated vaccines and live vaccines. The inactivated vaccine is made by purifying the viruses cultured in an embryonated egg and deactivating them with formalin or the like. The vaccines include a whole virus vaccine in which entire inactivated viruses are utilized, a split vaccine in which a viral envelopes are pulverized with ether etc., and a subunit vaccine in which hemagglutinin and neuramidase components are purified, etc. As for the live vaccine, a live attenuated influenza vaccine (LAIV) has been developed and used. Because the whole virus vaccine causes side effects in children, they are currently not used globally including Korea, but used only in some countries. On the other hand, component vaccines such as split vaccines and subunit vaccines are widely used due to their safety and acknowledged effectiveness. In addition, a vaccine containing an adjuvant such as MF-59 to enhance the immune response or a virosome vaccine which forms virus-like vesicles has been developed and used in some countries. Antibodies against specific influenza virus obtained through natural infection or vaccination do not form protective antibodies against influenza viruses of other subtypes and cannot exhibit sufficient immunogenicity against new variants of an antigen. Since influenza viruses have big and small mutations every year, the epidemic strain changes every year. Therefore, it is hard to expect the effect of the vaccination in the previous year, and the vaccination should be conducted every year.
Globally, influenza virus is a serious and constant threat to human health. Each year, 3 to 5 million people show severe symptoms by the infection and 500,000 people die, and a seasonal influenza epidemic could potentially kill millions. Antagonists to the virus surface glycoprotein, neuraminidase, have been widely used for the treatment of influenza infections, but their efficacy has been drastically decreased by drug-resistant viral mutants. Vaccine is the most effective way to prevent influenza virus infection, but as mentioned above, the protective efficacy of the vaccine is not optimized for high-risk groups such as patients with weak immunity, e.g., pediatric and elderly people. In addition, post-vaccination immunity typically responds specifically to a new variant, but the influenza virus rapidly changes, and thus, new vaccine should be produced almost every year. The determination of the antigenic composition of the vaccine is based on the anticipation of a variant that will be prevalent in the new year. Therefore, vaccines are ineffective if a vaccine variant is different from epidemic variant. As a result, there is desperate need for vaccines having new preventive and therapeutic effects that can exhibit broad protection against influenza viruses.
Immunization against influenza virus is mediated almost by neutralizing antibodies targeting hemagglutinin (HA). Identification of an antigenic position in hemagglutinin means to find the immunologically predominant hemagglutinin head domain (HA1) which mediates entry of influenza viruses into a host cell by attaching to sialic acid receptors. Studies using anti-HA head domain monoclonal antibodies indicate that this type of antibodies blocks the attachment of the virus to the sialic acid on the host cell surface, thereby preventing the virus from entering into the cell. However, due to high mutation rates and tolerance for antigenic changes in the hemagglutinin head domain, antibodies targeting the hemagglutinin head domain are only effective against very similar variants. As such, a broader range of antibodies targeting the receptor attachment site is not structurally discovered. In contrast, antibodies which are attached to the hemagglutinin stem domain (HA2) adjacent to the cell membrane block the major structural rearrangement of HA essential for the fusion of the viruses with the endosomal membranes of the host, thereby blocking the entry of the viruses into the cell. Amino acid sequences of the HA stem domain is relatively well conserved in various influenza strains due to less mutations than the head domain. However, due to the diversity of antigenic stimuli found in the hemagglutinin head domain, it is known that most monoclonal antibodies targeting the stem domain generally neutralize only specific single virus.
However, not many studies have been conducted yet on broadly versatile neutralizing monoclonal antibodies (bNAbs) that can neutralize various subtypes of influenza viruses. Therefore, there is a desperate need for a new vaccine that can be used as a broadly versatile vaccine for various subtypes.